Inhibition of Dihydroorotate Dehydrogenase Activity by Brequinar Sodium
作者： Davette L. Behrens , Frank W. Perrella , Shih-Fong Chen , Lisa M. Papp
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摘要: Abstract The novel anticancer drug candidate brequinar sodium (DuP 785, NSC 368390, 6-fluoro-2-(2′-fluoro-1,1′-biphenyl-4-yl)-3-methyl-4-quinoline-carboxylic acid salt) was shown previously to be an inhibitor of dihydroorotate dehydrogenase, the fourth enzyme de novo pyrimidine biosynthetic pathway. Brequinar inhibits activity this isolated from mammalian sources only but not those forms yeast or bacteria, which also use ubiquinone as cofactor. does inhibit a soluble Zymobacterium oroticum dehydrogenase uses NAD+ L1210 with mixed inhibition kinetics respect either substrate (dihydroorotate) cofactor (ubiquinone Q6) K1′ values in 5–8 nm range. Our results suggest that by binding at unique site is distinct ubiquinone-binding site. This appears enzyme, because yeast, Escherichia coli, Z. enzyme.
aacrjournals.org参考文章(17)
R.W. Miller, [9] Dihydroorotate dehydrogenase (Neurospora) Methods in Enzymology. ,vol. 51, pp. 63- 69 ,(1978) , 10.1016/S0076-6879(78)51011-2
W.W Cleland, The kinetics of enzyme-catalyzed reactions with two or more substrates or products: III. Prediction of initial velocity and inhibition patterns by inspection Biochimica et Biophysica Acta. ,vol. 67, pp. 188- 196 ,(1963) , 10.1016/0006-3002(63)91816-X
V Hines, L D Keys, M Johnston, Purification and properties of the bovine liver mitochondrial dihydroorotate dehydrogenase Journal of Biological Chemistry. ,vol. 261, pp. 11386- 11392 ,(1986) , 10.1016/S0021-9258(18)67396-X
Doris Karibian, Dihydroorotate dehydrogenase (Escherichia coli). Methods in Enzymology. ,vol. 51, pp. 58- 63 ,(1978) , 10.1016/S0076-6879(78)51010-0
Daniel L. Dexter, Shih-Fong Chen, Regina L. Ruben, Mechanism of Action of the Novel Anticancer Agent 6-Fluoro-2-(2′-fluoro-1,1′-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic Acid Sodium Salt (NSC 368390): Inhibition of de Novo Pyrimidine Nucleotide Biosynthesis Cancer Research. ,vol. 46, pp. 5014- 5019 ,(1986)
Robert J. Ardecky, Barbara M. DeLarco, Kenneth D. Paull, Martin Forbes, Daniel L. Dexter, V. L. Narayanan, Jacqueline Plowman, Davette L. Tippett, Betsy A. Dusak, David P. Hesson, Ganti V. Rao, Activity of a Novel 4-Quinolinecarboxylic Acid, NSC 368390 [6-Fluoro-2-(2′-fluoro-1,1′-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic Acid Sodium Salt], against Experimental Tumors Cancer Research. ,vol. 45, pp. 5563- 5568 ,(1985)
Robert A. Pascal, Christopher T. Walsh, Mechanistic studies with deuterated dihydroorotates on the dihydroorotate oxidase from Crithidia fasciculata. Biochemistry. ,vol. 23, pp. 2745- 2752 ,(1984) , 10.1021/BI00307A033
Frank W. Perrella, EZ-FIT: a practical curve-fitting microcomputer program for the analysis of enzyme kinetic data on IBM-PC compatible computers Analytical Biochemistry. ,vol. 174, pp. 437- 447 ,(1988) , 10.1016/0003-2697(88)90042-5
Jane-Jane Chen, Mary Ellen Jones, The cellular location of dihydroorotate dehydrogenase: Relation to de novo biosynthesis of pyrimidines Archives of Biochemistry and Biophysics. ,vol. 176, pp. 82- 90 ,(1976) , 10.1016/0003-9861(76)90143-0
Kottarappat N. Dileepan, James Kennedy, Rapid conversion of newly-synthesized orotate to uridine-5-monophosphate by rat liver cytosolic enzymes FEBS Letters. ,vol. 153, pp. 1- 5 ,(1983) , 10.1016/0014-5793(83)80107-0